Healthy digestion requires coordinated movements of the stomach and intestines to mix food with digestive enzymes, to stir the nutrients so they approach the intestinal wall for absorption into the body, and to propel the intestinal contents through the digestive tract. The movement of the walls of the gastrointestinal (GI) tract and their contents is called gastrointestinal motility. Gastrointestinal motility is controlled by the nerves and muscles within the gastrointestinal tract.
The normal patterns of the nerves and muscles are influenced every day by many factors. Sleeping and waking changes motility, as does exercise. Emotional distress can also have profound effects on gastrointestinal motility. Even the food that you eat releases substances into the blood which influence motility. Nerve connections between the brain and the GI tract send messages in both directions. These modify not only GI motility, but also perceptions from the gut.
Motility disorders occur when the nerves in the gastrointestinal tract are missing, immature, or damaged by infections or toxins. Disorders can also occur when the nerves are adversely influenced by chemical substances from inside the body (such as the chemicals released during an inflammation caused by Crohn's disease), or outside the body (such as opiates given for pain). In this case, the nerves and muscles of the GI tract do not function in a strong or coordinated fashion. Motility disorders may also occur when the GI muscles are diseased—either from a genetic defect (such as some forms of muscular dystrophy) or an acquired disorder (such as progressive systemic sclerosis and amyloidosis). In this case, the coordinated contractions produced by the GI muscles are too weak to move the intestinal contents.
Symptoms soon arise when there are abnormalities in the strength or coordination of contractions. Sometimes the symptoms are accompanied by evidence of growth failure or tissue damage. The symptoms may vary depending on the location and severity of the abnormalities. Heartburn and constipation are common symptoms of motility disorders. Other frequent complaints include: chronic vomiting, nausea, cramping, bloating, abdominal distention and diarrhea after eating.
The most common motility disturbance is a troublesome but relatively benign condition called “irritable bowel syndrome” (IBS). It accounts for 50 percent of all patients who see a GI specialist.
The primary function of the gastrointestinal tract is to absorb ingested nutrients. This is achieved when transit along the esophagus and gastrointestinal tract is at a rate which facilitates optimal digestion and absorption of water and electrolytes. Abnormal patterns in gastrointestinal motility result in number of disorders ranging from diffuse esophageal spasm (an esophageal obstructive disorder by dysphagia), achalasia (an obstructive disorder in which the lower esophageal sphincter fails to relax adequately resulting in dysphagia) and pain due to functional bowel disorders such as irritable bowel syndrome (IBS), non-ulcer dyspepsia, and idiopathic constipation.
Gastrointestinal distress presents itself as discomfort associated with an intestinal disorder by symptoms of diarrhea and flatulence or gas. Diarrhea is the abnormally frequent passage of watery stool. Diarrhea may have a variety of causes including bacteria or viral induced diarrhea. Travelers diarrhea, for example, is also believed to be of microbial origin. Diarrhea may also be a side effect of drug administration, particularly antibiotics. Diarrhea may be induced by food intolerance which is caused by allergy or the ingestion of foods that are excessively fatty, spicy, or contain a high degree of fermentable carbohydrate, roughage or a large number of seeds. Food intolerance may also be brought on by a preformed toxin in the food thus causing food poisoning. Other conditions and diseases can also cause diarrhea, and diarrhea may only be one of many symptoms associated with a major illness.
Diarrhea is thus a symptom of an intestinal disorder or other bodily function and symptomatic relief can be accomplished by the use of various prescription and nonprescription products. The active ingredients in these products include trimebutine, loperamide, attapulgite, bismuth subsalicylate, diphenoxylate HCl, polycarbophil, calcium polycarbophil and mixtures thereof.
Flatulence or intestinal gas is another intestinal disorder which contributes to gastrointestinal distress. Such gas exists as trapped gas bubbles which manifest itself by feelings of pain, bloating and cramping in the abdominal area.
While various products exist for treating diarrhea and gas simultaneously, no product has heretofore been proposed for treating the combination of the symptoms of both diarrhea and gas which contains trimebutine in combination with simethicone.
Trimebutine belongs to the class of medications called spasmolytics and it is a noncompetitive spasmolytic. Trimebutine is a prokinetic agent that acts directly on the smooth muscle of the GI tract and it is known to regulate abnormal intestinal activity. It is used to treat irritable bowel syndrome (spastic colon). This condition is caused by overactive movements of the bowels. Trimebutine works by slowing down the movements of the bowel. The actions of trimebutine [3,4,5-trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutylester] on the gastrointestinal tract are mediated via (i) an agonist effect on peripheral μ, δ and κ opiate receptors and (ii) release of gastrointestinal peptides such as motilin and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and glucagon. Trimebutine accelerates gastric emptying, induces premature phase III of the migrating motor complex in the intestine and modulates the contractile activity of the colon. Recently, trimebutine has also been shown to decrease reflexes induced by distension of the gut lumen in animals and it may therefore modulate visceral sensitivity. Clinically, trimebutine has proved to be effective in the treatment of both acute and chronic abdominal pain in patients with functional bowel disorders, especially irritable bowel syndrome, at doses ranging from 300 to 600 mg/day. It is also effective in children presenting with abdominal pain.
Additionally, trimebutine has been used in many countries since 1969 for the treatment of functional bowel disorders, including irritable bowel syndrome (IBS). The efficacy of the compound to relieve abdominal pain has been demonstrated in various clinical studies using different protocols of treatment. Trimebutine given either intravenously or orally delays the appearance of a phase III of the migrating motor complex (MMC) in the stomach and the duodenum by inducing a premature phase III, migrating along the whole intestine. In man, trimebutine stimulates intestinal motility in both fed and fasted states. More recently, trimebutine has been shown to be able to influence the activity of visceral afferents by decreasing the intensity of the recto-colonic reflex in rats as evidenced by the inhibition of colonic motility consecutive to rectal distension. This result may be related to the beneficial effects found with trimebutine in patients with IBS and more specifically in the treatment of attacks of abdominal pain.
Trimebutine is a medicine that acts on the peripheral encephalinergic receptors, specially digestive receptors and therefore it is a regulator of digestive motility. Normally, trimebutine is administered in solid form, injectable dissolution, suppository and reconstitutable powder for preparation of a drinkable suspension. Another form of trimebutine includes prolonged release which has been the object of French Patent No FR 2,640,876. The oral forms of trimebutine are indicated in the treatment of pains related to functional distress, the alimentary canal and the biliary routes, as well as in the treatment of pain or intestinal functional distress. Among the proposed oral forms, the drinkable suspension is more particularly adapted to pediatric use.
On the other hand, simethicone has been used in diverse therapeutic liquid and solid forms of metering. Most of the normal formulations of metering of simethicone are antacid diverse combinations of simethicone with separated. According to it, it is necessary to separate simethicone of the antacid to avoid the inactivación of simethicone. Other formulations of simethicone in the literature have been suggested such as simethicone and dextromethorphan, as well as a combination of simethicone, a tranquilizer and an antacid. According to the prior art, it is possible to combine simethicone with an antacid, antidiarrheal or an antiperistaltic agent to provide lessening of gastrointestinal pain. See for example, EP-A-0428296 and EP-A-0014253. Nevertheless, when formulating simethicone with antidiarrheals, antiperistaltic and histamine H2 antagonist, it has been discovered that without taking special precautions, the speed of dissolution of the antidiarrheals, antiperistaltic and histamine H2 antagonist occurs in an adverse manner.